Research Status and Outlook of PD-1/PD-L1 Inhibitors for Cancer Therapy

Abstract

PD-1/PD-L1 inhibitors are a group of immune checkpoint inhibitors as front-line treatment of multiple types of cancer. However, the serious immune-related adverse reactions limited the clinical application of PD-1/PD-L1 monoclonal antibodies, despite the promising curative effects. Therefore, it is urgent to develop novel inhibitors, such as small molecules, peptides or macrocycles, targeting the PD-1/PD-L1 axis to meet the increasing clinical demands. Our review discussed the mechanism of action of PD-1/PD-L1 inhibitors and presented clinical trials of currently approved PD-1/PD-L1 targeted drugs and the incidence of related adverse reactions, helping clinicians pay more attention to them, better formulate their intervention and resolution strategies. At last, some new inhibitors whose patent have been published are listed, which provide development ideas and judgment basis for the efficacy and safety of novel PD-1/PD-L1 inhibitors.

Keywords: PD-1; PD-L1; adverse events; clinical trials; immune checkpoint inhibitors; monoclonal antibody.

Figure 1

The expression of PD-1 and PD-L1 at different cell types at physiological condition and in tumors.

Figure 2

Mechanism of anti-tumor immune surveillance and PD-1/PD-L1 inhibitors. (A) Shows that PD-L1 is highly expressed in tumor cells and tumor-related APCs, while PD-1 is highly expressed in tumor-infiltrating lymphocytes. The combination of PD-L1 and PD-1 can inhibit the activation, proliferation and anti-tumor function of CD8⁺ T cells and realize tumor immune escape. (B) Shows that after antibody treatment, anti-PD-1 will bind to PD-1, preventing PD-1 from binding to PD-L1 or PD-L2, and anti-PD-L1 will bind to PD-L1, blocking the binding of PD-L1 to PD-1 and B7-1, releasing the tumor-specific killing ability of T cells.

Figure 3

The general structures of small molecules in 2018: general structure 1 represents 1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives.

Figure 4

The general structures of small molecules in 2019: general structure 6 represents 2,8-diacyl-2,8-diazaspiro [5.5] undecane compounds; general structure 7, 20 and 21 represent heterocyclic compounds; general structure 22 and 23 represent noncondensed pyridines; general structure 27 represents a class of indolines.

Figure 5

The general structures of small molecules in 2020: general structure 28 represents biphenyl compounds.

Figure 6

The general structures of peptides: general structure 29, 31 and 32 represent synthetic peptide; general structure 30 represents peptidomimetic compounds.

Figure 7

The general structures of macrocycles: general structure 33 and 34 represent macrocyclic compounds; general structure 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45 and 46 represent macrocyclic peptides.